PROJECT SUMMARY Each year in the U.S., approximately 2 million people experienced myocardial ischemia (inadequate blood supply to heart muscle). Ischemic heart disease is a common cause of heart failure. Currently, about 1.6 million post-ischemia survivors live with ischemic heart failure, a deadly condition without effective treatment. The main function of the heart is to pump out blood to supply the body with nutrients and oxygen. Sarcomeric proteins make up the molecular motor of the heart muscle, which are essential for heart function. Modifications on sarcomeric proteins play a central role in regulating heart function in various physiological and diseased conditions. The long-term goal of our lab is to understand how modifications on sarcomeric proteins affect heart function in ischemia and the consequent ischemic heart failure. The effort will lead to potential new therapeutic strategies or biomarkers for the deadly heart diseases. The present proposal focuses on one of the key sarcomeric protein regulators, called cardiac troponin I (cTnI). Recently, we have found that its modifications are significantly altered in the patients with ischemic heart failure as well as the heart failure resulting from genetic heart muscle diseases. The preliminary study has shown that one crucial cTnI modification site protects heart from ischemia-related injury and is kept at a high level of modification in the consequent ischemic heart failure. The proposed study will address the question: how the cTnI modification protects heart function from ischemia-related injury. There are two specific aims: 1) to investigate the molecular and cellular cardioprotective mechanism conveyed by the cTnI modification; 2) to test whether the protective function is unique to the proposed site. The proposed project has broad impacts; it will not only produce knowledge about heart function regulation and ischemic heart disease but also help the principal investigator build strong research program at Morgan State University, a prestigious member of Historically Black Colleges and Universities, in order to promote the workforce diversity in biomedical field and health care.